Polymer-based systems capable of in situ gelation are potentially useful in treating surgical or traumatic disruption of organs, connective tissue, muscles, tendons and membranes. Injectable materials that can effectively seal or suture internal wounds (e.g., needle holes, necrotic spaces, arthritic cavities) to achieve tissue approximation for better wound healing would be desirable. Such systems must meet five crucial requirements: safety, efficacy, usability, cost, and regulatory approval. In particular, they must show adequate adhesion with underlying tissue, biocompatibility and biodegradability, and shelf stability. Among the available United States FDA-approved materials, hyaluronic acid (HA) holds a prominent role. The HA present in living organisms is found primarily in extracellular and pericellular matrices, is highly hydrated, biocompatible, and non-immunogenic. These features, along with its degradability by native enzymes (hyaluronidases), make it potentially useful as a matrix component or visco-supplementation element in regenerative medicine.
Injectable HA-based materials can be filled into defects of any shape and cross-linked in situ. Known cross-linkable HA materials show good adhesion to the native tissues, affording good physicochemical interlocking and a cohesive polymer-tissue interface. A number of chemistries have been employed to design in situ gelable HA-based materials, such as: Schiff reaction between amine and aldehyde groups (for example as described in Tan, H., et al., Controlled gelation and degradation rates of injectable hyaluronic acid-based hydrogels through a double crosslinking strategy. J Tissue Eng Regen Med, 2011. 5(10): p. 790-7); Michael-type addition between thiols and diacrylates or other Michael-type acceptors (for example as described in Dong, Y., et al., Thermoresponsive hyperbranched copolymer with multi acrylate functionality for in situ cross-linkable hyaluronic acid composite semi-IPN hydrogel. J Mater Sci Mater Med, 2012. 23(1): p. 25-35); nucleophilic substitutions on haloacetates (for example as described in Serban, M. A. and G. D. Prestwich, Synthesis of hyaluronan haloacetates and biology of novel cross-linker-free synthetic extracellular matrix hydrogels. Biomacromolecules, 2007. 8(9): p. 2821-8; formation of disulphide bridges (for example as described in Shu, X. Z., et al., Disulfide-crosslinked hyaluronan-gelatin hydrogel films: a covalent mimic of the extracellular matrix for in vitro cell growth. Biomaterials, 2003. 24(21): p. 3825-34; free radical photopolymerization upon (meth)acrylic residues (for example as described in Park, Y. D., N. Tirelli, and J. A. Hubbell, Photopolymerized hyaluronic acid-based hydrogels and interpenetrating networks. Biomaterials, 2003. 24(6): p. 893-900; Huygens “click” reactions between azides and alkynes; and phenols (tyramines) that spontaneously cross-link after their enzymatic oxidation to catechols (for example as described in Jin, R., et al., Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. Biomaterials, 2007. 28(18): p. 2791-800).
The previously known cross-linked matrices have been used in a variety of ways, from cartilage replacement and prevention of post-surgical issues to controlled release of biotherapeutics. These previously known modifications generally preserve HA sensitivity to hyaluronidases, thus allowing enzyme-mediated degradation of the hydrogels. However, the gelation kinetics and the biocompatibility of these previously developed reactive materials are not optimal. In some instances, the known HA modifications and reagents have shown some cytotoxicity. Another issue with the known compositions is presented by the kinetics, wherein in some cases gelation proceeds too quickly to enable proper filling of the target space before the gelation occurs. Gelation rate can in principle be controlled by acting on the amount of polymer precursor and/or cross-linker concentration. This, however, can adversely affect the mechanical properties of the resulting gel and hence its therapeutic value.
Therefore, there remains a continuing need in the art for HA-based in situ gelable systems capable of forming a resistant gel with slower kinetics, so as to enable a more homogeneous crosslinking and cavity filling, would be ideal for biomedical uses.